1. Field of Invention
The present invention relates to compositions and methods for treating penile erectile dysfunctions, such as male erectile impotence, and more particularly, to compositions and methods for the topical administration to the penis effective for the treatment of penile erectile dysfunctions.
2. Background of the Invention
Impotence is generally characterized as the inability to develop or sustain an erection sufficient to conclude coitus. Many men are afflicted with a degree of impotence resulting from psychological and physiological conditions. Causes of impotence are numerous. These include atonic, due to paralysis of the motor nerves (nervi erigentes) without any evidence of lesion to the central nervous system. Conversely, it could be paretic as a result of a lesion in the central nervous system, particularly the spinal cord. Alternatively, it could be psychic, and dependent on a mental complex or instability. The cause may also be symptomatic, due to some other disorder, such as injury to nerves in the perineal region, by virtue of which the sensory portion of their erection reflex is blocked out. (See, e.g., U.S. Pat. No. 4,801,587.)
Specific physiological disorders which may be the cause of penile erectile dysfunction or male impotence, and for which the present invention may be used, in addition to psychological causes, include, for example, pelvic vascular disease, diabetes mellitus, neurodegenerative disorders, side effects of medication, pelvic surgery, trauma, and the like.
One widely used solution for treating impotency involves implants which, in essence, are internal prostheses. However, implants, which often include surgery, are expensive and not always effective.
The other major solution for treating male impotence is via use of drugs. Since erection necessarily involves vasodilation of the arteries of the penis, the pathophysiologic basis of impotence can often be treated by vasodilation agents. There have been and are ongoing clinical and experimental research efforts to develop new and better drugs and delivery routes for such drugs. These efforts have been the subject of several literature articles and issued patents including, for example, the following United States Patents: U.S. Pat. No. 4,801,587--Voss, et al; U.S. Pat. No. 5,256,652--El-Rashidy; U.S. Pat. No. 5,336,678--Cavallini; U.S. Pat. No. 5,583,144--Kral; U.S. Pat. No. 5,475,535--Place, et al; U.S. Pat. No. 5,482,039--Place; U.S. Pat. No. 5,451,609--Bellamy, et al; U.S. Pat. No. 5,242,391--Place, et al; U.S. Pat. No. 5,145,852--Virag; U.S. Pat. No. 5,399,581--Laragh; U.S. Pat. No. 5,270,323--Milne, et al; U.S. Pat. No. 5,236,904--Gerstenberg, et al; U.S. Pat. No. 4,127,118--Latorre; U.S. Pat. No. 5,565,466--Gioco, et al; U.S. Pat. No. 5,492,911--Stief; U.S. Pat. No. 5,594,032--Gonzalez-Cadavid, et al; U.S. Pat. No. 5,488,059--Buhl; U.S. Pat. No. 5,439,938--Snyder, et al.
While the interested reader should refer directly to the above patents and the patents and literature discussed or cited in these patents, as well as the literature discussed below, the following brief discussion is provided.
U.S. Pat. No. 5,583,144 is based on the use of piperoxan for treatment of erectile impotence and includes a disclosure of topical administration. The combination of piperoxan with prostaglandins, particularly PGE2, is disclosed. The compositions for topical administration include gels, (including hydrogels), ointments, creams, etc. but without any details.
Generally, however, the patent art reveals that topical or transdermal application of the treating agent is not available or preferred: U.S. Pat. No. 5,451,609 (injection per intracavernosal route); U.S. Pat. No. 5,242,391 (urethral insert); U.S. Pat. No. 5,145,582 (PGE1 with papaverine); U.S. Pat. No. 5,399,581 (enteral); U.S. Pat. Nos. 5,270,323; 5,236,904 (intracavernosal injection); and U.S. Pat. No. 4,127,118 (injection).
Patents which disclose topical (transdermal) formulations include U.S. Pat. No. 5,256,652 ('652) and U.S. Pat. No. 5,336,678 ('678). The '678 patent is directed to the topical administration of from 0.1 to 10% minoxidil. Patentees divide the drugs for treating erectile impotence into three class:
1) oral, e.g., yohimbine; PA1 2) intracavernous injection, e.g., PGE1; PA1 3) topical, e.g., nitroglycerin. PA1 (a) a pharmacologically effective amount of prostaglandin E.sub.1 ; PA1 (b) an effective amount of a skin penetration enhancing compound selected from the group consisting of C.sub.6 to C.sub.20 -hydrocarbyl group substituted 1,3-dioxane, 1,3-dioxolane and acetal; PA1 (c) a pharmaceutically effective carrier comprising PA1 (d) a gelling effective amount of a gelling agent; and, optionally, PA1 (e) an anti-irritating effective amount of menthol. PA1 R'.sub.1 and R'.sub.2, each, independently, represent C.sub.1 to C.sub.4 aliphatic group.
The '652 patent describes a topical composition which includes an absorption enhancer and, optionally, a vasoconstrictor and an alpha receptor blocker. The enhancer is a cyclodextrin, particularly, hydroxypropyl-beta-cyclodextrin (HPBCD).
The '652 patent refers to U.S. Pat. No. 4,311,707 ('707) as disclosing topical administration of prostaglandins including an alleged use to treat impotency. U.S. Pat. No. 4,801,857 ('857) is also discussed in the '652 patent. This patent discloses a topical ointment for treating impotence.
Other references which may be of interest include: U.S. Pat. No. 5,587,167 (topical composition with extract of ginseng radix for prophylaxis and treatment of premature ejaculation); U.S. Pat. No. 5,565,466 (modulating the human sexual response by oral mucosal, intranasal or rectal administration of vasodilator); U.S. Pat. No. 5,492,911 (Linsidomine, alone or in combination with, prostaglandins, for injection); U.S. Pat. No. 5,447,920 (cosmetic composition, inclusion product of HPBCD); U.S. Pat. No. 5,594,032 (inducible Nitric Oxide Synthase (NOS) agents; non-topical modes); U.S. Pat. No. 5,488,059 (pyridylguanidine compound by injection into corpus cavernosum or transdermal); and U.S. Pat. No. 5,439,938 (inhibitors for NOS, topical application).
Transdermal delivery of prostaglandins has been the subject of scientific study. In a report titled "Aspects of the transdermal delivery of prostaglandins" by A. C. Watkinson, et al, International J. of Pharmaceutics, 74:229-236, 1991, the authors studied in vitro skin penetration through human skin for prostaglandins E.sub.1, E.sub.2, F.sub.1a, and F.sub.2a and the influence of absorption rates using the enhancers Azone.RTM. and Transcutol (2-ethoxy-ethoxy ethanol). Preapplication of the enhancer to the skin was found to facilitate drug flux. However, the enhancement for PGE-1 was not as significant as for PGE-2. The greatest enhancement was found after pretreatment with a mixture of Azone and Transcutol, approximately 10% after 48 hours.
Although topical nitroglycerin, minoxidil, papaverine and prostaglandin E.sub.1 (PGE-1) have been studied, their efficacy, as documented in the scientific literature, has been wanting. Anderson, et al, "Topical Nitrate Treatment of Impotence", Ann. Pharmacotherapy, 27:1203-1205, 1993, provide a review of the earlier literature and their conclusion is that there is insufficient evidence that topical application is efficacious. Kim and McVary, "Topical Prostaglandin-E1 for the Treatment of Erectile Dysfunction", J. Urol 158:1828-1830, 1995a, reported only 20% (2 of 10) of patients treated with a topical gel containing 0.4% PGE-1 had erections with intermediate rigidity. The carrier of the topical gel is not described. The authors concluded that the PGE-1 gel resulted in a significant increase in cavernous artery diameter and peak systolic flow velocity and appeared to be well tolerated after genitalia and forearm application. However, the results of topical absorption were not conclusive. It is further stated that, "Prostaglandin-E1 gel may have promise at higher concentrations, with different skin enhancers or in combination with other topical agents." Further investigation was deemed warranted.
In another study, significant increases in erectile response were seen after topical application of 0.5% PGE-1 and 67% of the patients achieved rigidity consistent with penetration. However, the erections did not persist after the end of stimulation (Montorsi, et al, Drugs 50(3):465-479, 1995a; Intern. J. Impotence Res. 7:10, 1995b). In neither of these reports were there noted any adverse events attributable to the application of PGE-1. It was suggested that an increased penetration of the active agent through the skin and/or into the erectile tissues may be required to have an improved response.
In the case of papaverine, topical application to the penis of 133 to 500 milligrams (mg) of an aqueous gel containing papaverine hydrochloride in concentrations of 7, 15 or 20% was studied (Kim, et al, J. Urol 158:361-365, 1995b). The 15% and 20% formulations elevated cavernosal arterial diameter (by about 36%) and peak systolic blood flow (by about 26%) in patients with spinal injury. However, while three of the seventeen patients treated had tumescence and erections, they also likewise responded following application of a placebo gel. Nevertheless, erections after the papaverine gel lasted longer, although this result was not statistically significant.
Gomaa, et al. (British Med. Journal 312:1512-5, 1995) reports that a topical formula ("cream") containing three actives (3% aminophylline, 0.25% isosorbide dinitrate and 0.05% co-dergocrine mesylate) is effective in the treatment of erectile dysfunction.
Becher, et al, in an Abstract ("A Double Blinded Placebo Controlled Trial of Topical Prostaglandin E1 for Erectile Dysfunction") presented at the Erectile Dysfunction Symposium held in San Francisco, Calif., in February 1997, reported that in three pilot studies using three different formulations on 51 impotent patients 33% (5 of 15) responded to a formulation with 2 mg PGE-1, as compared to 13% responding to the placebo; 61% (11 of 18) responded to a formulation with 4 mg PGE-1, as compared to 39% responding to placebo; and 66% (12 of 18) responded to a formulation containing 4 mg PGE-1 and nitroglycerin, as compared to 39% responding to placebo. In these studies, one patient developed a skin rash and one had an episode of hypotension. The compositions used in the trials are not described.
Linet, et al, The New England J. of Medicine, 334(14):873-877 (Apr. 4, 1996) describes a study on the efficacy and safety of alprostadil administered by intracavernosal injection for treatment of erectile dysfunction in men. Among other side effects 54 of the 235 men (23 percent) experienced penile pain. Alprostadil is a synthetic prostaglandin E.sub.1. In an accompanying editorial (L. Lipshultz, pages 913-14) the Linet study was described as the "largest prospective, multi-institutional study thus far undertaken of the injection of a single drug. (footnote omitted.) The authors not unexpectedly found that alprostadil produced significantly better erections than placebo and that the response was dose-dependent." The editorial goes on to explain that of the 577 men studied, 69 percent completed the six-month study; 87 percent reported that the injections resulted in satisfactory sexual activity. Of the 31 percent that did not complete the study lack of efficiency was a prominent complaint. 683 men were evaluated for side effects and 50 percent reported penile pain. In a different study using alprostadil 17 percent discontinued therapy because of severe pain with an additional 22 percent having mild-to-moderate pain. Dr. Lipshultz concludes that intracavernous injections are a well-accepted and efficacious treatment for erectile dysfunction whereas, "o!ther ways of administering alprostadil, such as by a medicated urethral system (footnote omitted) and in a topical gel,.sup.10 have not yet been demonstrated to have similar results." Footnote 10 was to the above article by Kim and Mcvary (1995a).
In an even more recent study of treatment of erectile dysfunction with alprostadil, Padma-Nathan, et al, The New England J. of Medicine, 336(1):1-7, Jan. 2, 1997, a transurethral delivery mechanism was used. Nearly 88% of the 996 men in the study completed the entire three-month treatment period. The transurethral administration of alprostadil was found to be effective in 69% of the men in the alprostadil group. However, penile pain (categorized as mild) was reported by almost 36% of the men during the clinical testing while over 2% discontinued the study because of the pain. In the home treatment phase penile pain was reported after 10.8% of the alprostadil administrations and by nearly 33% of the men. These authors refer, at page 6, to alternative methods of delivery, including an intraurethral cream containing prostaglandin E.sub.2 applied to the urethral meatus. Of the 20 men in this study full penile tumescence was reported to have occurred in 30 percent of the subjects. The authors also refer to the Kim and McVary pilot study of transdermal PGE-1 as failing to induce rigid erections, apparently because of insufficient transfer of the drug through skin.
It is known from U.S. Pat. No. 4,861,764 to Carlos M. Samour and Stefanous Daskalakis (and commonly assigned with the subject application) that 1,3-dioxolanes and 1,3-dioxanes, including, for example, 2-n-pentyl-, 2-n-heptyl-, 2-n-nonyl-, 2-n-undecyl-, pentylene-1,5-bis- 1,3-dioxolanes; 2-n-nonyl-, 2-n-undecyl-, 2-(2',6'-dimethyl-2'-heptadienyl)- 1,3-dioxanes; are useful as percutaneous absorption enhancers for enhancing skin penetration of therapeutic agents.
As described more recently in the partially commonly assigned U.S. Pat. No. 5,527,797 to Eisenberg and Samour, the above 1,3-dioxanes, 1,3-dioxolanes and other alkyl or alkenyl substituted compounds of general formula R-X (where R is a C.sub.5 to C.sub.28 alkyl or alkenyl; X is 1,3-dioxane; 1,3-dioxolane; 5-, 6-, 7-, or 8-numbered lactam; cycloalkylene carbonate, --COOH, --OH, cycloalkylene carbonate; --COOR' (R' is a lower alkyl or unsaturated lower alkyl); --(OCH.sub.2 CH.sub.2).sub.n --OH (n is an integer of from 1 to about 20); --OC(O)R'; R'OC(O)--; --C(O)N(R').sub.2 ; acetals; and hemiacetals; can be used as water-insoluble or substantially water-insoluble stratum corneum-lipid modifiers for enhancing transportation of charged molecules through skin by iontophoresis.
Recently issued U.S. Pat. No. 5,620,980 to C. Samour, also commonly assigned with this application, discloses the use of the 1,3-dioxolanes and 1,3-dioxanes in a topical formulation containing minoxidil for treating hair loss.
There is no suggestion in the prior art, as described above, which would have led the practitioner to understand or believe that the 1,3-dioxolanes and 1,3-dioxanes or acetals would have been effective for enhancing penetration of prostaglandins, especially, prostaglandin E.sub.1 (PGE-1), or any other vasodilating agent or other drug effective for use in the treatment of erectile dysfunction. In fact, the use of these skin penetration enhancing compounds in combination with PGE-1, phentolamine, prazosin, etc., can be considered to be contra-indicated by the prior art.
For example, though the dioxanes and dioxolanes are known as penetration enhancers, delivery of elevated drug levels via a non-vascular route directly into target sites deep below the skin was not to be expected. The well-vascularized dermis would be expected to rapidly remove a drug before it can penetrate into the deeper target tissues, in this case, the corpora cavernosa and spongiosum. Furthermore, the cavernosa are covered by a thick tissue, the tunica albuginea, whose barrier properties are very different from that of the skin.
Secondly, the major barrier function of the skin, the stratum corneum, is virtually absent on the glans of the penis, which is the site of most likely maximum absorption because of its communication with the above mentioned corpora. Since the 1,3-dioxanes, 1,3-dioxolanes and acetals are well known as skin penetration enhancers whose mechanism of action is the temporary disruption of the stratum corneum, its enhancement of permeation of therapeutically active amounts of drug through this non-cornified organ structure would not have been expected.
Although not specifically addressed in the above mentioned prior art relating to topical formulations for treating erectile dysfunction, PGE-1 is substantially insoluble in water. Attempts to increase solubility by increasing the pH of the system are of limited use since the stability of PGE-1 decreases at pH levels above the pKa of the free acid.
Accordingly, it is an object of the invention to provide a prostaglandin composition effective for topical delivery in the treatment of penile erectile dysfunction.
It is a related object to provide a topical formulation for transdermal delivery which is more effective than known formulations and easier to use than injectable formulations or implants.
Still another object of the invention is to provide a topical composition for transdermal delivery of active agent for treatment of penile erectile dysfunction wherein the composition may be applied to only the glans of the penis.